Bisphenol A Binds to Ras Proteins and Competes with Guanine Nucleotide Exchange: Implications for GTPase-Selective Antagonists
详细信息 查看全文
- 作者：Miriam Sch枚pel ; Katharina F. G. Jockers ; Peter M. D眉ppe ; Jasmin Autzen ; Veena N. Potheraveedu ; Semra Ince ; King Tuo Yip ; Rolf Heumann ; Christian Herrmann ; J眉rgen Scherkenbeck ; Raphael Stoll
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：December 12, 2013
- 年：2013
- 卷：56
- 期：23
- 页码：9664-9672
- 全文大小：519K
- 年卷期：v.56,no.23(December 12, 2013)
- ISSN：1520-4804
文摘
We show for the first time that bisphenol A (10) has the capacity to interact directly with K-Ras and that Rheb weakly binds to bisphenol A (10) and 4,4鈥?biphenol derivatives. We have characterized these interactions at atomic resolution suggesting that these compounds sterically interfere with the Sos-mediated nucleotide exchange in H- and K-Ras. We show that 4,4鈥?biphenol (5) selectively inhibits Rheb signaling and induces cell death suggesting that this compound might be a novel candidate for treatment of tuberous sclerosis-mediated tumor growth. Our results propose a new mode of action for bisphenol A (10) that advocates a reduced exposure to this compound in our environment. Our data may lay the foundation for the future design of GTPase-selective antagonists with higher affinity to benefit of the treatment of cancer because K-Ras inhibition is regarded to be a promising strategy with a potential therapeutic window for targeting Sos in Ras-driven tumors.